The objective of this application is to develop new and improved scintimammography (SM) methods using To-99m labeled sestamibi for the diagnosis of breast cancer in patients with large amounts of breast glandular tissue. The application has four specific aims. Aim#1 is to develop a time-activity dual-view (lateral and craniocaudal) SM data acquisition method for breast imaging using a pinhole collimator. The design parameters of the pinhole collimator and the imaging configuration will be determined for optimal trade-off between spatial resolution, detection efficiency, field-of-view and patient comfort. Methods to compensate for attenuation, collimator-detector blur and scatter will be developed to improve the quantitative accuracy and quality of the time-sequence SM images. Aim #2 is to develop limited-angle and full-angle SPECT-SM methods using existing and potential new instrumentation for images with higher contrast than those obtainable from the dual-view SM. Aim #3 is to develop parametric analysis methods to derive the uptake and washout characteristics of sestamibi in benign and malignant breast lesions. In Aim #4, and initial exploratory study involving 100 patients is designed to determine design parameters of the pinhole collimator and acquisition parameters for the time-activity image data that will provide sufficient statistical power for the parametric analysis in Aim #3. A confirmatory study involving 300 patients will utilize the pinhole collimator and acquisition parameters determined in the exploratory study. It is designed to evaluate the accuracy of breast cancer diagnosis using the time-activity dual-view SM method as compared with conventional screen-film and digital x-ray mammography. The patients will be recruited for the study from tow clinical sites. The proposed research has several important innovations and benefits for the diagnosis of breast cancer. The project is targeted at younger patients with high density breasts who have been found difficult to image using conventional x-ray mammography. The proposed pinhole collimator design offers improved imaging characteristics over conventional parallel-hole collimator design. Its proposed imaging geometry allows both lateral and craniocaudal views of the breasts unattainable with conventional collimators. The parametric data derived from time- sequence images will provide valuable information in differentiating benign and malignant breast lesions. The potential of SPECT-SM methods will be explored. Since the proposed SM imaging methods can be implemented easily using current nuclear medicine instrumentation, the success of the project can significantly impact the diagnosis of breast cancer in younger patients.